Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019209 (hepatomegaly)
 5,798 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Liver regeneration is perhaps the most studied example of compensatory growth aimed to replace loss of tissue in an organ. Hepatocytes, the main functional cells of the liver, manage to proliferate to restore mass and to simultaneously deliver all functions hepatic functions necessary to maintain body homeostasis. They are the first cells to respond to regenerative stimuli triggered by mitogenic growth factor receptors MET (the hepatocyte growth factor receptor] and epidermal growth factor receptor and complemented by auxiliary mitogenic signals induced by other cytokines. Termination of liver regeneration is a complex process affected by integrin mediated signaling and it restores the organ to its original mass as determined by the needs of the body (hepatostat function). When hepatocytes cannot proliferate, progenitor cells derived from the biliary epithelium transdifferentiate to restore the hepatocyte compartment. In a reverse situation, hepatocytes can also transdifferentiate to restore the biliary compartment. Several hormones and xenobiotics alter the hepatostat directly and induce an increase in liver to body weight ratio (augmentative hepatomegaly). The complex challenges of the liver toward body homeostasis are thus always preserved by complex but unfailing responses involving orchestrated signaling and affecting growth and differentiation of all hepatic cell types.
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PMID:Principles of liver regeneration and growth homeostasis. 2372 Feb 94

TCPOBOP (1,4-Bis [2-(3,5-Dichloropyridyloxy)] benzene) is a constitutive androstane receptor (CAR) agonist that induces robust hepatocyte proliferation and hepatomegaly without any liver injury or tissue loss. TCPOBOP-induced direct hyperplasia has been considered to be CAR-dependent with no evidence of involvement of cytokines or growth factor signaling. Receptor tyrosine kinases (RTKs), MET and epidermal growth factor receptor (EGFR), are known to play a critical role in liver regeneration after partial hepatectomy, but their role in TCPOBOP-induced direct hyperplasia, not yet explored, is investigated in the current study. Disruption of the RTK-mediated signaling was achieved using MET knockout (KO) mice along with Canertinib treatment for EGFR inhibition. Combined elimination of MET and EGFR signaling [MET KO + EGFR inhibitor (EGFRi)], but not individual disruption, dramatically reduced TCPOBOP-induced hepatomegaly and hepatocyte proliferation. TCPOBOP-driven CAR activation was not altered in [MET KO + EGFRi] mice, as measured by nuclear CAR translocation and analysis of typical CAR target genes. However, TCPOBOP-induced cell cycle activation was impaired in [MET KO + EGFRi] mice due to defective induction of cyclins, which regulate cell cycle initiation and progression. TCPOBOP-driven induction of FOXM1, a key transcriptional regulator of cell cycle progression during TCPOBOP-mediated hepatocyte proliferation, was greatly attenuated in [MET KO + EGFRi] mice. Interestingly, TCPOBOP treatment caused transient decline in hepatocyte nuclear factor 4 alpha expression concomitant to proliferative response; this was not seen in [MET KO + EGFRi] mice. Transcriptomic profiling revealed the vast majority (~40%) of TCPOBOP-dependent genes primarily related to proliferative response, but not to drug metabolism, were differentially expressed in [MET KO + EGFRi] mice. Conclusion: Taken together, combined disruption of EGFR and MET signaling lead to dramatic impairment of TCPOBOP-induced proliferative response without altering CAR activation.
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PMID:TCPOBOP-Induced Hepatomegaly and Hepatocyte Proliferation are Attenuated by Combined Disruption of MET and EGFR Signaling. 2988 1